Rosalba Lembo

Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial

IMPORTANCE No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. OBJECTIVE To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. INTERVENTIONS Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 μg/kg/min (range, 0.025-0.3 µg/kg/min). MAIN OUTCOMES AND MEASURES The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. RESULTS The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001). CONCLUSIONS AND RELEVANCE Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00621790.

Levosimendan for Hemodynamic Support after Cardiac Surgery

BACKGROUND Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta‐analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery. METHODS We conducted a multicenter, randomized, double‐blind, placebo‐controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 μg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30‐day mortality. RESULTS The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30‐day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], ‐5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, ‐2 hours; 95% CI, ‐5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, ‐12 hours; 95% CI, ‐21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, ‐1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias. CONCLUSIONS In patients who required perioperative hemodynamic support after cardiac surgery, low‐dose levosimendan in addition to standard care did not result in lower 30‐day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825.)

Mortality in multicenter critical care trials: An analysis of interventions with a significant effect

Objectives:We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians’ opinion and usual practice for the selected interventions. Data Sources:MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. Study Selection:We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. Data Extraction:For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. Data Synthesis:We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. Conclusions:We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.

Concomitant implantation of Impella® on top of veno‐arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock

Veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) support stabilizes patients with cardiogenic shock. Despite improved oxygenation and peripheral circulation, LV unloading may be impeded due to the increased afterload, resulting in a failing static left ventricle and in high mortality.

The Fragility Index in Multicenter Randomized Controlled Critical Care Trials.

Objectives: Recent literature has drawn attention to the potential inadequacy of frequentist analysis and threshold p values as tools for reporting outcomes in clinical trials. The fragility index, which is a measure of how many events the statistical significance of a result depends on, has been suggested as a means to aid the interpretation of trial results. This study aimed to calculate the fragility index of clinical trials in critical care medicine reporting a statistically significant effect on mortality (increasing or decreasing mortality). Data Sources: Literature search (PubMed/MEDLINE) to identify all multicenter randomized controlled trials in critical care medicine. Study Selection: We identified 862 trials; of which 56 fulfilled eligibility criteria and were included in our analysis. Data Extraction: Calculation of fragility index for trials reporting a statistically significant effect on mortality, and analysis of the relationship between trial characteristics and fragility index. Data Synthesis: The median fragility index was 2 (interquartile range, 1–3.5), and greater than 40% of trials had a fragility index of less than or equal to 1. 12.5% of trials reported loss to follow-up greater than their fragility index. Trial sample size was positively correlated, and reported p value was negatively correlated, with fragility index. Conclusions: In critical care trials reporting statistically significant effects on mortality, the findings often depend on a small number of events. Critical care clinicians should be wary of basing decisions on trials with a low fragility index. We advocate the reporting of fragility index for future trials in critical care to aid interpretation and decision making by clinicians.

Randomized Evidence for Reduction of Perioperative Mortality: An Updated Consensus Process

OBJECTIVE Of the 230 million patients undergoing major surgical procedures every year, more than 1 million will die within 30 days. Thus, any nonsurgical interventions that help reduce perioperative mortality might save thousands of lives. The authors have updated a previous consensus process to identify all the nonsurgical interventions, supported by randomized evidence, that may help reduce perioperative mortality. DESIGN AND SETTING A web-based international consensus conference. PARTICIPANTS The study comprised 500 clinicians from 61 countries. INTERVENTIONS A systematic literature search was performed to identify published literature about nonsurgical interventions, supported by randomized evidence, showing a statistically significant impact on mortality. A consensus conference of experts discussed eligible papers. The interventions identified by the conference then were submitted to colleagues worldwide through a web-based survey. MEASUREMENTS AND MAIN RESULTS The authors identified 11 interventions contributing to increased survival (perioperative hemodynamic optimization, neuraxial anesthesia, noninvasive ventilation, tranexamic acid, selective decontamination of the gastrointestinal tract, insulin for tight glycemic control, preoperative intra-aortic balloon pump, leuko-depleted red blood cells transfusion, levosimendan, volatile agents, and remote ischemic preconditioning) and 2 interventions showing increased mortality (beta-blocker therapy and aprotinin). Interventions then were voted on by participating clinicians. Percentages of agreement among clinicians in different countries differed significantly for 6 interventions, and a variable gap between evidence and clinical practice was noted. CONCLUSIONS The authors identified 13 nonsurgical interventions that may decrease or increase perioperative mortality, with variable agreement by clinicians. Such interventions may be optimal candidates for investigation in high-quality trials and discussion in international guidelines to reduce perioperative mortality.

Comparison of renal perfusion solutions during thoracoabdominal aortic aneurysm repair

BACKGROUND To determine whether renal perfusion with cold crystalloid solution enriched with histidine-tryptophan-ketoglutarate (Custodiol; Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) provides better protection against renal ischemic injury than cold lactated Ringers solution in patients undergoing thoracoabdominal aortic aneurysm open repair. METHODS We analyzed a prospectively compiled database containing all 111 consecutive patients who underwent thoracoabdominal aortic aneurysm open repair at our center from 2008 to 2011. A cohort of 104 consecutive patients was identified of which 50 (48%) had renal perfusion with Custodiol and 54 (52%) with lactated Ringers solution. Propensity score matching based on baseline clinical variables, which were expected to influence renal outcomes, was performed to correct for any bias that may have been associated with the use of Custodiol. Acute kidney injury (AKI) as defined by Kidney Disease Improving Global Outcomes guidelines and perioperative estimated glomerular filtration rate were compared in the two groups. Independent predictors of AKI were also identified by multivariate analysis. RESULTS After propensity score matching, we were able to match 42 Custodiol cases one-to-one with those receiving perfusion with lactated Ringers solution. Overall 30-day mortality was 5.9%; temporary hemodialysis or continuous veno-venous hemofiltration was needed in 4.8% of the patients without any case of dialysis at discharge. Freedom from AKI was significantly increased in the Custodiol group (38.1% vs 9.5%; P = .002) despite longer total renal ischemic time (51.5 ± 16.4 minutes vs 43.6 ± 16.0 minutes; P = .05). By analysis of variance for repeated measures, a significant upward trend of perioperative estimated glomerular filtration rate was observed in the Custodiol group (group × time interaction = F3,66; P < .001), and by multivariate analysis, Custodiol perfusion was the only independent predictor of non-AKI (P = .04). CONCLUSIONS The use of Custodiol was safe and provided improved perioperative renal function compared with lactated Ringers solution. Randomized trials are needed to confirm these data and to assess their clinical consequences.

Severe Intra-aortic Balloon Pump Complications: A Single-Center 12-Year Experience

OBJECTIVE An intra-aortic balloon pump (IABP) is used routinely in high-risk patients undergoing cardiac surgery to prevent or treat low-cardiac-output syndrome and to reduce perioperative mortality. The insertion and management of IABP carry the risk of major vascular complications. The authors reviewed their database to ascertain the incidence of IABP-related severe complications. DESIGN A retrospective study. SETTING A teaching hospital. PARTICIPANTS Ten thousand three hundred sixty-five patients scheduled for elective or emergency cardiac surgery over a 12-year period at a single center. INTERVENTIONS Four hundred twenty-three patients received an IABP perioperatively. Careful preoperative screening for peripheral arterial disease, strict postoperative control, and the sheathless insertion technique to spare the arterial flow to the lower limb were performed routinely. MEASUREMENTS AND MAIN RESULTS The use of a perioperative IABP was 0.7% at the beginning of the observation period in 1999 and 7.3% in 2010, showing a fluctuating trend. Two patients (0.47%) died of direct complications, arterial wall damage and bleeding. Immediate surgical exploration and control of bleeding were followed by multiple-organ failure and death. Vascular complications, leading to lower-limb ischemia, occurred in 4 of 423 patients (0.94%). All of them underwent urgent vascular surgery and survived. Local sepsis occurred in 2 other patients (0.47%). CONCLUSIONS These data indicate that an IABP is a valuable option in high-risk patients undergoing cardiac surgery even if not devoid of intrinsic risks for vascular complications (0.94%), septic complications (0.47%) and mortality (0.47%).

A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design

OBJECTIVE Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes. DESIGN Double-blind, placebo-controlled, multicenter randomized trial. SETTING Tertiary care hospitals. INTERVENTIONS Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours. MEASUREMENTS AND MAIN RESULTS The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction. CONCLUSIONS This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.

Do Patients Undergoing MitraClip Implantation Require Routine ICU Admission

OBJECTIVES Because of its reduced invasiveness, MitraClip (Abbott Vascular, Menlo Park, CA) therapy usually is reserved for patients with extreme left ventricular dysfunction or severe comorbidity contraindicating surgery. The appropriate post-procedural care in this high-risk population is yet to be defined. In this study, the postoperative course of such patients is reported, focusing on early complications and need for intensive care unit (ICU) management. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of patients with severe mitral regurgitation undergoing transcatheter mitral valve repair with the MitraClip system in the authors institution was performed. INTERVENTIONS One hundred thirty patients underwent MitraClip implantation between 2008 and 2012. At the end of the procedure, all patients were admitted to the ICU. MEASUREMENTS AND MAIN RESULTS Median ICU stay was 0.98 (0.82-1.87) days. Median mechanical ventilation time was 9.5 (6.8-14.1) hours. One hundred one patients (78%) required inotropic support and 13 patients (10%) suffered cardiogenic shock and required intra-aortic balloon pump support. No patient died during the procedure, but 3 patients died in the ICU. Three postoperative course profiles were identified: Fast-track, overnight stay, and critical illness. Twenty-four patients (18.5%) had an uneventful postoperative course, 89 patients (68.5%) suffered minor complications, and 17 patients (13.1%) required intensive care management and organ support. Preoperative serum creatinine (odds ratio [OR] 1.8; p = 0.014), cardiogenic shock (OR 34,8; p = 0.002), ventricular tachycardia (OR 2.8; p = 0.03), and intra procedural inotropes (OR 4; p = 0.001) were correlated with a complicated postoperative course. CONCLUSIONS A large number of patients undergoing MitraClip could be managed with a fast-track ICU course; however, it still is difficult to predict the postoperative course based on preoperative characteristics.